Approximately 750,000 patients develop ischemic stroke in the US annually, of which about 150,000 of the incidents are fatal. Notwithstanding more than 50 years of effort (Zivin, J. A. 1999. Neurology 53, 14-19), the thrombolytic agent, tissue-type plasminogen activator (tPA) remains the only FDA-approved treatment for acute stroke. However, its brief therapeutic window and the high incidence of post-treatment complications including intracranial hemorrhage (ICH) has limited the clinical use of tPA to approximately 3% of all patients presenting with symptoms of stroke (Lapchak, P. A. 2002. Curr Neurol Neurosci Rep. 2, 1-6; Nagai, N. et al. 2001. Blood 97, 3086-3092). Preventing the adverse effects of tPA on the central nervous system (CNS) is likely to enhance the benefits of treatment and provide new approaches to ameliorate the impact of stroke.
The deleterious effects of tPA may not be related exclusively to its proteolytic activity. The inventor of the present invention and co-workers have previously reported that exogenous tPA decreases cerebral vascular resistance in rats (Nassar, T. et al. 2004. Blood 103, 897-902) and piglets (Armstead, W. M. et al. 2004. J Neurotrauma 21, 1204-1211); that the levels of tPA in the CNS are elevated after fluid percussion brain injury (FPI), which is thought to mimic concussive traumatic brain injury (Gennarrelli, T. A. 1994. J Neurotrauma 11, 357-368); and that administration of tPA at the examined concentrations induces cerebral vasodilation in naïve animals (Nassar, T. et al. 2004, supra; Armstead, W. M. et al. 2004, supra; Armstead, W. et al. 2005. Develop Brain Res, 156, 139-146).
International Patent Application Publication No. WO 03/006042 to the inventor of the present invention discloses a six amino acid peptide derived from plasminogen activator-1 (PAI-1) having the amino acid sequence EEIIMD which is capable of reducing the undesirable side effects such as intracerebral hemorrhage induced by fibrinolytic agents, e.g., tPA, uPA, tcuPA, streptokinase, rt-PA or alteplase, rt-PA derivatives or anisoylated streptokinase complex. In the protocol disclosed, the peptide was introduced into the thrombolytic regimen in later stages to prevent the vasoactive or side effects of the primary fibrinolytic agent. It was further reported that PAI-1 and the PAI-1 derived peptide EEIIMD inhibit tPA-mediated signal transduction (Akkawi, S. et al. 2006. Am J Physiol Heart Circ Physiol. 291, H1351-1359) without compromising its catalytic activity.
International Patent Application Publication No. WO 03/095476 to the inventor of the present invention teaches administration of the peptide EEIIMD of SEQ ID NO: 11, or the peptide acetyl-RMAPEEIIMDRPFLYVVR-amide of SEQ ID NO: 2, anti-LRP antibodies or LRP antagonists, in combination with one or more fibrinolytic agents for enhancing the fibrinolytic activity, reducing the side effects due to vasoactivity caused by the fibrinolytic agents, and/or prolonging the half lives of the fibrinolytic agents. That invention further relates to combination compositions and/or therapy regimens comprising the polypeptide EEIIMD of SEQ ID NO: 11 and/or the Ac-RMAPEEIIMDRPFLYVVR-amide peptide of SEQ ID NO: 2 and one or more currently used plasminogen activators.
U.S. Patent Application Publication No. US2006/0069035 to the inventor of the present invention discloses that the EEIIMD of SEQ ID NO: 11 peptide reduces the effective dosage of a thrombolytic agent required in the prevention or treatment of thromboembolic disorders. This in turn reduces the risk for side effects of the thrombolytic agents, the side effects being manifested in the late stage of therapy.
International Application Publication No. WO 2008/018084 to Higazi and Cines discloses the use of the peptide EEIIMD of SEQ ID NO: 11 and 6-mer peptide analogs thereof in preventing neuronal damage and in treating brain injury.
There is still an unmet need for improved, highly effective means for treating thromboembolic disorders, particularly those related to ischemic stroke, and neurological diseases.